Lung cancer is the leading cause of cancer-related mortality throughout the world. Approximately 80%-85% of all lung cancers are non-small cell lung cancer (NSCLC), which include squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Current treatment options include surgical resection, platinum-based doublet chemotherapy with 3rd generation chemotherapy including gemcitabine, docetaxel, paclitaxel, vinorelbine, irinotecan, or pemetrexed, and radiation therapy alone or in combination. Despite these therapies, the disease is rarely curable and prognosis is dismal, with an overall 5-year survival rate of only 15%.
The EGFR inhibitor therapy, have been extensively studied either alone or in combination with cytotoxic chemotherapy in NSCLC. However, the results overall show very small improvements in survival. The cumulative data from clinical trials with EGFR inhibitors suggest that different patients derive different degrees of clinical benefit from the treatment with EGFR inhibitors. These drugs have been shown to elicit partial responses in 10-20% of NSCLC patients (Fukuoko et al. J. Clin. Oncol, 21:2237-2246 (2003) and Kris et al. JAMA, 290:2149-2158 (2003)). Of those NSCLC patients harboring EGFR mutations and on EGFR-TKI therapy, 70-75% show a positive response rate (see, e.g. Yano et al., Cancer Res., 68:9479-9487 (2008)). However, 25-30% of the patients are intrinsically resistant to EGFR-TKIs. Moreover, even those patients who are initial responders to treatment acquire resistance with time.
cMET inhibitor therapy is also under development for treating NSCLC because overexpression, activation and sometimes mutation of cMET have been detected in NSCLC cell lines and tumor tissues. For instance, 41-72% of lung tumors from patients with primary tumors exhibited increased cMet expression, and 8-13% of the tumors carried MET mutations. In addition, studies have shown that elevated expression of activated cMet significantly correlated to a shorter time to progression (TTP) in patients with NSCLC (Zucali et al., Ann. Oncol., 19:1605-12 (2008)).
The implication of cMet signaling in tumor growth and progression has led to the development of a variety of anticancer drugs aimed at blocking cMet signaling. Holmes et al. (J. Mol. Biol., 367:395-408, (2007)) describes that the N-terminus of HGF can bind, but not activate cMet signaling, suggesting that this may be an effective method of antagonizing the cMet pathway. Examples of current c-Met drugs under development include neutralizing antibodies such as MAG102 (Amgen) and MetMab (Roche), and tyrosine kinase inhibitors (TKIs) such as ARQ 197, XL 184, PF-02341066, GSK1363089/XL880, INC280, MP470, MGCD265, SGX523, PF04217903 and JNJ38877605. Preliminary clinical results of several of these drug agents have been encouraging.
The invention is based, in-part, on the surprising discovery of a method for identifying patients with NSCLC who will most likely benefit from EGFR inhibitor therapy and/or cMET inhibitor therapy. The methods of the invention can also be used to determine whether a patient receiving EGFR inhibitor therapy has acquired drug resistance.